[ Chest Infections CHEST Reviews ]

Treatment of Community-Acquired
Pneumonia in Immunocompromised
Adults
A Consensus Statement Regarding Initial Strategies
Julio A. Ramirez, MD; Daniel M. Musher, MD; Scott E. Evans, MD; Charles Dela Cruz, MD; Kristina A. Crothers, MD;
Chadi A. Hage, MD; Stefano Aliberti, MD; Antonio Anzueto, MD; Francisco Arancibia, MD; Forest Arnold, DO;
Elie Azoulay, MD; Francesco Blasi, MD; Jose Bordon, MD; Steven Burdette, MD; Bin Cao, MD; Rodrigo Cavallazzi, MD;
James Chalmers, MD; Patrick Charles, MD; Jean Chastre, MD; Yann-Erick Claessens, MD; Nathan Dean, MD;
Xavier Duval, MD; Muriel Fartoukh, MD; Charles Feldman, MD; Thomas File, MD; Filipe Froes, MD;
Stephen Furmanek, MPH; Martin Gnoni, MD; Gustavo Lopardo, MD; Carlos Luna, MD; Takaya Maruyama, MD;
Rosario Menendez, MD; Mark Metersky, MD; Donna Mildvan, MD; Eric Mortensen, MD; Michael S. Niederman, MD;
Mathias Pletz, MD; Jordi Rello, MD; Marcos I. Restrepo, MD; Yuichiro Shindo, MD; Antoni Torres, MD;
Grant Waterer, MD; Brandon Webb, MD; Tobias Welte, MD; Martin Witzenrath, MD; and Richard Wunderink, MD

BACKGROUND: Community-acquired pneumonia (CAP) guidelines have improved the treat-

ment and outcomes of patients with CAP, primarily by standardization of initial empirical
therapy. But current society-published guidelines exclude immunocompromised patients.
RESEARCH QUESTION: There is no consensus regarding the initial treatment of immuno-
compromised patients with suspected CAP.
STUDY DESIGN AND METHODS: This consensus document was created by a multidisciplinary
panel of 45 physicians with experience in the treatment of CAP in immunocompromised
patients. The Delphi survey methodology was used to reach consensus.
RESULTS: The panel focused on 21 questions addressing initial management strategies. The panel
achieved consensus in defining the population, site of care, likely pathogens, microbiologic
workup, general principles of empirical therapy, and empirical therapy for specific pathogens.
This document offers general suggestions for the initial treatment of the
INTERPRETATION:
immunocompromised patient who arrives at the hospital with pneumonia.
CHEST 2020; 158(5):1896-1911

KEY WORDS: community-acquired pneumonia; immunocompromised; pneumonia

FOR EDITORIAL COMMENT, SEE PAGE 1802; FOR RELATED ARTICLE, SEE PAGE 1912

ABBREVIATIONS: CAP = community-acquired pneumonia; CMV =
cytomegalovirus; MDR = multiple drug resistant; MRSA = methicillin-
resistant Staphylococcus aureus; NTM = nontuberculous mycobacteria;
PCP = Pneumocystis jirovecii pneumonia; TMP-SMX = trimethoprim-
sulfamethoxazole; TNF = tumor necrosis factor
AFFILIATIONS: From the Division of Infectious Diseases (Drs Ram-
irez, Arnold, and Gnoni, and Mr Furmanek), University of Louisville,
Louisville, KY; the Baylor College of Medicine and Michael E. DeBakey
VA Medical Center (Dr Musher), Houston, TX; the Department of
Pulmonary Medicine (Dr Evans), University of Texas MD Anderson
Cancer Center, Houston, TX; Pulmonary, Critical Care and Sleep
Medicine (Dr Dela Cruz), Yale University, New Haven, CT; the
Veterans Puget Sound Health Care System (Dr Crothers), University of
Washington, Seattle WA; the Thoracic Transplant Program (Dr Hage),
Indiana University, Indianapolis, IN; the Department of Pathophysi-
ology and Transplantation (Drs Aliberti and Blasi), University of
Milan, and Fondazione IRCCS Cà Granda Ospedale Maggiore Poli-
clinico, Respiratory Unit and Cystic Fibrosis Adult Center, Milan, Italy;
the South Texas Veterans Health Care System (Drs Anzueto and
Restrepo), Audie L. Murphy Memorial Veterans Hospital, and Uni-
versity of Texas Health, San Antonio, TX; the Pneumology Service (Dr
Arancibia), Instituto Nacional del Tórax and Clínica Santa María,
Santiago de Chile, Chile; the Medical ICU (Dr Azoulay), Saint-Louis
Teaching Hospital, Assistance Publique-Hôpitaux de Paris

1896 CHEST Reviews [ 158#5 CHEST NOVEMBER 2020 ]


(APHP), Paris, France; the Section of Infectious Diseases (Dr Bordon),
Providence Health Center, Washington, DC; the Wright State Uni-
versity Boonshoft School of Medicine (Dr Burdette), Dayton, OH; the
Department of Pulmonary and Critical Care Medicine (Dr Cao),
Center of Respiratory Medicine, National Clinical Research Center for
Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China;
the Division of Pulmonary, Critical Care, and Sleep Disorders Medi-
cine (Dr Cavallazzi), University of Louisville, Louisville, KY; the
Scottish Centre for Respiratory Research (Dr Chalmers), School of
Medicine, Ninewells Hospital and Medical School, Dundee, UK; the
Department of Infectious Diseases (Dr Charles), Austin Health and
Department of Medicine, University of Melbourne, Australia; the
Service de Médecine Intensive-Réanimation (Dr Chastre), Hôpital La
Pitié-Salpêtrière, Sorbonne Université, APHP, Paris, France; the
Department of Emergency Medicine (Dr Claessens), Centre Hospi-
talier Princesse Grace, Monaco; the Intermountain Medical Center and
the University of Utah (Dr Dean), Salt Lake City, UT; the UMR 1137,
IAME, INSERM (Dr Duval), and CIC 1425, Hôpital Bichat-Claude
Bernard, APHP, Paris, France; the Service de Médecine Intensive
Réanimation (Dr Fartoukh), Hôpital Tenon, APHP, and APHP, Sor-
bonne Université, Faculté de Médecine Sorbonne Université, Paris,
France; the Department of Internal Medicine (Dr Feldman), Faculty of
Health Sciences, University of the Witwatersrand, Johannesburg, South
Africa; the Infectious Disease Section (Dr File), Northeast Ohio
Medical University and Infectious Disease Division, Summa Health,
Akron, OH; the ICU, Chest Department (Dr Froes), Hospital Pulido
Valente-Centro Hospitalar Universitário Lisboa Norte, Lisbon,
Portugal; the Fundación del Centro de Estudios Infectológicos (Dr
Lopardo), Buenos Aires, Argentina; the Pulmonary Diseases Division
(Dr Luna), Universidad de Buenos Aires, Buenos Aires, Argentina; the
Department of Respiratory Medicine (Dr Maruyama), National Hos-
pital Organization Mie National Hospital, Tsu, Japan; the Pneumology
Department (Dr Menendez), La Fe University and Polytechnic Hos-
pital, La Fe Health Research Institute, Valencia, Spain; the Division of
Pulmonary, Critical Care and Sleep Medicine and Center for Bron-
chiectasis Care (Dr Metersky), University of Connecticut Health,
Farmington, CT; the Icahn School of Medicine at Mount Sinai (Dr
Mildvan), New York, NY; the Department of Medicine (Dr Morten-
sen), University of Connecticut Health Center, Farmington, CT; Pul-
monary and Critical Care (Dr Niederman), New York Presbyterian/
Weill Cornell Medical Center and Weill Cornell Medical College, New
York, NY; the Institute for Infectious Diseases and Infection Control
(Dr Pletz), Jena University Hospital, Jena, Germany; the Centro de
Investigacion Biomedica en Red de Enfermedades Respiratorias (Dr
Rello), Instituto de Salud Carlos III, and Infections Area, Vall d’Hebron
Institute of Research, Barcelona, Spain; the Department of Respiratory
Medicine (Dr Shindo), Nagoya University Graduate School of Medi-
cine, Nagoya, Japan; the Servei de Pneumologia (Dr Torres), Hospital
Clinic, Universitat de Barcelona. Barcelona, CIBERES, Spain; the
School of Medicine (Dr Waterer), University of Western Australia,
Perth, Australia; the Division of Infectious Diseases and Clinical
Epidemiology (Dr Webb), Intermountain Healthcare, Salt Lake City,
UT and Division of Infectious Diseases and Geographic Medicine,
Stanford Medicine, Palo Alto, CA; the German Center for Lung
Research (Dr Welte), Biomedical Research in Endstage and Obstruc-
tive Lung Disease Hannover (BREATH) Clinic of Pneumology,
Hannover Medical School, Hannover, Germany; the Division of Pul-
monary Inflammation and Department of Infectious Diseases and
Respiratory Medicine (Dr Witzenrath), Charité-Universitätsmedizin
Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and
Berlin Institute of Health, Berlin, Germany; and Pulmonary and
Critical Care (Dr Wunderink), Northwestern University Feinberg
School of Medicine, Chicago, IL.
FUNDING/SUPPORT: Sponsored by the International Respiratory
Infection Society.
CORRESPONDENCE TO: Julio A. Ramirez, MD, Division of Infectious
Diseases, University of Louisville, 501 E Broadway, Ste 100, Louisville,
KY 40202; e-mail: j.ramirez@louisville.edu
Copyright Ó 2020 Published by Elsevier Inc under license from the
American College of Chest Physicians.
DOI: https://doi.org/10.1016/j.chest.2020.05.598
chestjournal.org
Guidelines for the treatment of patients with
community-acquired pneumonia (CAP) have been
published by medical societies from several countries.
These guidelines have improved the treatment and
outcomes of patients with CAP, primarily by
standardization of initial empirical therapy. But current
society-published CAP guidelines exclude
immunocompromised patients.1-3
Immunocompromised patients have been excluded from
guidelines because of their need for complex, often
individualized, treatment, the expanded spectrum of
potential pathogens, and their exclusion from the large
prospective studies of antibiotic efficacy used to support
guideline recommendations.
The number of immunocompromised people at risk for
CAP is increasing, due to (1) longer survival of patients
with cancer, and recipients of organ transplants; (2)
better recognition of immunocompromising conditions;
(3) additional risk groups, such as those receiving novel
immune-modulating therapies for nonmalignant
diseases; and (4) approval of newer immunomodulatory
agents. It is estimated that 3% of the adult population of
the United States is immunosuppressed.4
Immunocompromising conditions are present in
approximately 20% to 30% of hospitalized patients with
CAP.5-7
Frequently, the initial treatment of pneumonia in
immunocompromised patients may not occur in
specialized tertiary care centers with advanced expertise
in their care. Rather, immunocompromised patients
with symptoms of lower respiratory tract infection often
present first to general hospitals to be treated by ED
physicians, internists, or hospitalists. These general
conditions are identical to those motivating the initial
impetus for guidelines to treat CAP; namely, the
frequency of the condition and the presentation of
patients in many different health-care settings
throughout the community.
Early and adequate empirical treatment of CAP in the
general population is associated with decreased
morbidity and mortality, and the authors attempt here
to facilitate application of these same principles to
patients at high risk of CAP-related complications due
to preexisting immune dysfunction. The approaches
suggested in this document are based on an extensive
review of the literature and on the collective experience
of the authors. A challenge in reviewing the CAP
literature on the immunocompromised host is that most
publications evaluate outcomes of antimicrobial therapy
1897
for patients in whom the pathogen causing CAP has
been identified. No large, prospective clinical studies
comparing different empirical therapies in
immunocompromised patients exist.
Susceptibility to specific infections varies widely in
immunocompromised patients and depends both on the
degree of immune suppression and the components of
Methods
The Delphi survey methodology was used to reach consensus. After a
full review of the English literature on the topic of treatment of CAP in
the immunocompromised patient, the Delphi questions used in the
survey were developed (Table 1). The following 5-point Likert scale
was used to evaluate agreement or disagreement with each proposed
answer: strongly disagree (1), disagree (2), neutral (3), agree (4),
strongly agree (5). It was considered that a consensus was reached
once more than 75% of participants agreed or strongly agreed with a
particular suggestion.
In each round of the Delphi survey, questions regarding the treatment
of CAP in the immunocompromised patient were submitted to all 45
participants in the consensus process. To anonymously record
participant responses and comments, a survey was developed using
Research Electronic Data Capture (REDCap), which allowed
participants to answer with their level of agreement with the
suggestion, and to write specific comments regarding the
management suggested by the group. After each round, all responses
were summarized and an anonymized summary of all the comments
was produced and sent to each participant. Participants had the
Results
A. Definition of Population
Question 1: Which patients with CAP should be
considered immunocompromised?
We suggest that patients with CAP should be considered
to be immunocompromised if they have an underlying
disease or medical treatment that alters the immune
system to the point that they are at elevated risk of
pneumonia not only by common organisms but also by
uncommon avirulent or opportunistic organisms.
No consensus exists regarding which patients should be
formally considered immunocompromised. Our
pragmatic approach is to consider patients to be
immunocompromised if they are at elevated risk of
pneumonia not only by common organisms but also by
uncommon avirulent or opportunistic organisms.
Several practical aspects of meeting this definition
include the need for comprehensive microbiologic
testing, the need to alter empirical antimicrobial therapy,
and the need for adjunctive therapy. Even using this
more restrictive definition, medical advances supporting
1898 CHEST Reviews
the immune system that are affected by the underlying
disease and/or medical therapy. In this document we
attempt to develop a unifying approach to simplify a
very complex topic, involving a heterogeneous
population. The objective of this document is to suggest
an approach to the initial treatment of
immunocompromised patients with suspected CAP.
opportunity to revise their earlier answers, considering the
anonymized replies of other members of the panel.
After the participants answered the third round of all questions, the
range of the answers decreased significantly and it was considered
that the group had reached consensus. At that point, a prefinal
manuscript was created and submitted to all participants for final
comments and agreement ratings. After the final comments were
incorporated, the manuscript was produced. Further details
regarding the Delphi survey methodology and rounds are to be
found in e-Appendix 1 in the online article.
Statistical Analysis
At each round of the survey, the mean and SD of agreement based on
the Likert scale for each question were calculated. To evaluate the level
of agreement or disagreement for each question in a manner that
incorporated both the mean and SD, a t-statistic for each question
was calculated. The t-statistic was used to identify which questions
had the least amount of agreement or the most controversy.
Agreement was visualized by bar charts, and final agreement was
reported as the percentage of participants who responded as Agree
or Strongly Agree.
longer survival of patients with serious conditions and
an expanding armamentarium of biological agents result
in expanding populations of at-risk individuals. Using
this approach, the most common acquired conditions
that qualify a patient as being immunocompromised are
a malignancy that suppresses immune responses (such
as lymphoma or leukemia) and advanced HIV infection
(CD4 T-lymphocyte count < 200 cells/mL). The most
frequent treatments that qualify a patient as being
immunocompromised include glucocorticoids, therapies
that suppress B-cell or T-cell responses, chemotherapy
for malignancy that causes neutropenia, conventional
disease-modifying antirheumatic drugs, and biological
agents used to treat a broad range of rheumatologic,
dermatologic, GI, and autoimmune diseases. Notably,
some agents (eg, ibrutinib, alemtuzumab, or fludarabine)
have persistent immunosuppressive effects, long after
active treatment is discontinued. Conditions indicating
that patients are immunocompromised are listed in
Table 2.8-13
Most patients who develop CAP have one or more
comorbid condition(s) that increase their susceptibility
[ 158#5 CHEST NOVEMBER 2020 ]
TABLE 1 ] Questions Addressing Initial Treatment Strategies for Immunocompromised Adults With Community-
Acquired Pneumonia
A. Definition of Population
Question 1: Which patients with CAP should be considered immunocompromised?
B. Site of Care
Question 2: Which immunocompromised patients with CAP should be admitted to the hospital?
C. Likely Pathogens
Question 3: What pathogens should be considered “core respiratory pathogens” in patients with CAP who are
immunocompromised?
Question 4: What pathogens should be considered beyond the core respiratory pathogens in patients with CAP who are
immunocompromised?
D. Microbiological Workup
Question 5: What microbiologic studies should be done in hospitalized patients with CAP who are immunocompromised?
Question 6: When should bronchoscopy with bronchoalveolar lavage be performed in hospitalized patients with CAP who are
immunocompromised?
Question 7: What microbiologic studies can be done with BAL fluid from hospitalized patients with CAP who are
immunocompromised?
E. Empirical Therapy: General Principles
Question 8: What empirical therapy should be started in hospitalized patients with CAP who are immunocompromised?
Question 9: In which patients with CAP who are immunocompromised should empirical therapy be extended beyond the core
respiratory pathogens?
Question 10: What role does the severity of pneumonia play in the selection of initial empirical therapy?
F. Empirical Therapy: Specific Pathogens
Question 11: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to MRSA?
Question 12: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to drug-resistant gram-negative bacilli, including Pseudomonas aeruginosa?
Question 13: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to multidrug-resistant (MDR) gram-negative bacilli?
Question 14: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to Pneumocystis jirovecii pneumonia (PCP)?
Question 15: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to Aspergillus?
Question 16: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to Mucorales?
Question 17: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to Nocardia?
Question 18: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to varicella-zoster virus?
Question 19: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to cytomegalovirus?
Question 20: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to Mycobacterium tuberculosis?
Question 21: In which immunocompromised patients should the initial empirical therapy be extended to cover the possibility
of CAP due to parasites?

CAP ¼ community-acquired pneumonia; MRSA ¼ methicillin-resistant Staphylococcus aureus.

to infection. From this perspective, patients with
common comorbid conditions such as diabetes,
chronic lung disease, liver disease, kidney disease, or
even those who are elderly and frail, can be
considered relatively immunocompromised. However,
patients with this degree of immune dysfunction are
typically infected with the same spectrum of
organisms that cause CAP in younger or healthier
adults, and their treatment is covered in the current
CAP guidelines.

chestjournal.org 1899
TABLE 2 ] Patient Conditions Qualifying Patients as Immunocompromised
Patient Condition References
Primary immune deficiency diseases .
Active malignancy or malignancy within 1 y of CAP, excluding patients with localized skin cancers or early-stage .
cancers (eg, stage 1 lung cancer)
Receiving cancer chemotherapy .
HIV infection with a CD4 T-lymphocyte count < 200 cells/mL or percentage < 14% a
8
Solid organ transplantation .
Hematopoietic stem cell transplantation .
Receiving corticosteroid therapy with a dose $ 20 mg prednisone or equivalent daily for $ 14 d or a cumulative 9, 10
dose > 600 mg of prednisoneb
Receiving biological immune modulatorsc 11, 12
Receiving disease-modifying antirheumatic drugs or other immunosuppressive drugs (eg, cyclosporin, 13
cyclophosphamide, hydroxychloroquine, methotrexate)

See Table 1 legend for expansion of abbreviation.

a
The association of HIV disease and CAP can be categorized in three levels: Level 1: Patients with a CD4 T-lymphocyte count > 500 cells/mL. These patients
are not at increased risk of CAP. Level 2: Patients with a CD4 T-lymphocyte count between 500 and 200 cells/mL. These patients are at increased risk of CAP,
but are not considered immunocompromised because the etiologic agents are the core CAP pathogens such as Streptococcus pneumoniae. Level 3: Patients
with a CD4 T-lymphocyte count < 200 cells/mL. These patients are at risk for CAP due to opportunistic pathogens such as Pneumocystis jirovecii. They are
considered immunocompromised patients with CAP.
b
In the case of patients taking steroid and who have CAP, both the daily dose and the cumulative dose of steroids should be considered. The association with
CAP can be define in three levels: Level 1: Doses # 10 mg of prednisone per day and a cumulative dose of less than 600 mg of prednisone or equivalent.
These patients are not at increased risk of CAP. Level 2: Doses 10 to # 20 mg of prednisone per day with a cumulative dose greater than 600 mg of
prednisone or equivalent at the time of the CAP episode. These patients are at increased risk of CAP, but are not considered immunocompromised because
the etiologic agents are the core CAP pathogens such as Streptococcus pneumoniae. Level 3: Doses $ 20 mg or more of prednisone per day with a
cumulative dose greater than 600 mg of prednisone or equivalent at the time of the CAP episode. These patients are at risk for CAP due to opportunistic
pathogens such as Pneumocystis jirovecii. They are considered immunocompromised patients with CAP. Because of the cumulative dose of at least 600 mg,
these patients need to have received steroid therapy for at least 3 to 4 wk to be considered as fulfilling this condition.
c
These drugs are used to treat a wide array of inflammatory conditions and have multiple immunologic targets. The diverse effects of these drugs include
interfering with cell signaling, inhibiting cytokine function, interrupting innate immunity, depleting B cells, or inhibiting T-cell activation. Specific dis-
cussion of these drugs in detail is beyond the scope of this article. However, nearly all immunomodulators carry some risk of infection. Because these
immunomodulating agents affect different components of the immune system, the risk for specific infections varies with the target of the
immunomodulator.

B. Site of Care infiltrate on chest radiography. A CT scan of the chest

Question 2: Which immunocompromised patients with
CAP should be admitted to the hospital?
We suggest that the decision for hospitalization should be
based on clinical judgment having a low threshold for
hospital admission.
In patients with CAP who are not
immunocompromised, the admission decision is based
on clinical judgment and can be supplemented by using
validated severity scores such as the Pneumonia Severity
Index or the CRB-65/CURB-65. Hospitalization of
immunocompromised patients with CAP is based
primarily on clinical judgment, considering that CAP
severity scores have not been well validated in
immunocompromised patients.14-16 Because
immunosuppressive drugs are known to modulate the
inflammatory response, the typical signs and symptoms
of CAP may be attenuated in these patients. The blunted
inflammatory response may not produce a clear
will allow better definition of the extent of pulmonary
infiltrate as well as better recognition of complications of
pneumonia such as abscesses or pleural effusions. This
information, gained by CT imaging of the chest, may
help in the decision regarding hospitalization. Hypoxia
is a particularly useful criterion to define site of care. In
nonimmunocompromised patients with CAP, blood
oxygen saturation < 92% is considered an appropriate
threshold for hospital admission.17
Immunocompromised patients may appear stable at the
time of the initial evaluation but may deteriorate rapidly,
progressing in a few hours from moderately severe
pneumonia to severe pneumonia in need of intensive
care. Also, the increased range of potential infecting
agents renders selection of any empirical regimen much
more challenging, often requiring parenteral agents.
Therefore, our suggestion is for a low threshold for
hospitalization. If the patient is considered sufficiently
stable for outpatient care, mechanisms for close follow-

1900 CHEST Reviews [ 158#5 CHEST NOVEMBER 2020 ]

up and rapid reentry to inpatient health care should be
available.
C. Likely Pathogens
Question 3: What pathogens should be considered “core
respiratory pathogens” in patients with CAP who are
immunocompromised?
We suggest that the list of core respiratory pathogens able
to cause CAP in the immunocompromised patient should
be the same as those for the nonimmunocompromised.
Immunocompromised patients are susceptible to
infection with the same respiratory viruses and bacteria
that cause CAP in nonimmunocompromised patients.
We call these “core respiratory pathogens.” Common
respiratory viral pathogens that cause mild upper
respiratory tract infections in healthy adults can lead to
severe lower respiratory tract infections in
immunocompromised patients. Table 3 lists the primary
groups of core respiratory pathogens that can cause CAP
in immunocompromised patients.5,6,18
Question 4: What pathogens should be considered beyond
the core respiratory pathogens in patients with CAP who
are immunocompromised?
We suggest to focus attention on respiratory pathogens
that may cause CAP in the immunocompromised patient
and for which antimicrobial therapy is available.
When considering likely etiologies of CAP beyond the
core respiratory pathogens, it is important to focus
attention on organisms that are amenable to
antimicrobial treatment. Common respiratory
pathogens that (1) may cause CAP in the
TABLE 3 ] Core Respiratory Pathogens That May Cause Community-Acquired Pneumonia in the Immunocom-
promised Patient
Gram-Positive Bacteria Gram-Negative Bacteria
Streptococcus Haemophilus influenzae
pneumoniae
Staphylococcus aureus Moraxella catarrhalis
(MSSA)
Streptococcus Enterobacteriaceae (eg, Klebsiella species,
pyogenes Escherichia coli)
Other streptococci
MSSA ¼ methicillin-susceptible Staphylococcus aureus.
chestjournal.org
immunocompromised host and (2) for which
antimicrobial therapy is available are listed in Table 4.
Different types of immunocompromising conditions will
predispose to different types of etiologic agents. A
description of specific immune deficiencies and the
associated respiratory pathogens are depicted in Table 5.
Initial empirical therapy active against these respiratory
pathogens may be necessary only in selected patients
presenting with specific epidemiologic, clinical, or
immunologic risk factors for infection due to a
particular pathogen. These risk factors and the specific
pathogens that are involved are discussed below.
D. Microbiological Workup
Question 5: What microbiologic studies should be done in
hospitalized patients with CAP who are
immunocompromised?
We suggest a comprehensive microbiological workup with
the goal to perform pathogen-directed therapy and
deescalation of therapy.
A critical aspect of the treatment of these patients is an
initial microbiologic workup coupled with empirical
therapy, followed by a deescalation to therapy directed
to the causative pathogen. Deescalation of therapy is
important because continuing broad-spectrum therapy
for the full duration of therapy is associated with
selection of multidrug-resistant organisms, increased
risk of toxicity, drug-drug interactions, and impaired
antimicrobial stewardship for the entire community. As
the primary way to perform deescalation therapy is by
knowing which pathogen is causing the pneumonia, a
comprehensive microbiologic workup is critically
“Atypical” Bacteria Respiratory Viruses
Legionella Influenza virus
pneumophila
Chlamydophila Parainfluenza virus
pneumoniae
Mycoplasma Coronavirus
pneumoniae
Coxiella burnetii Respiratory
syncytial virus
Rhinovirus
Adenovirus
Human
metapneumovirus
1901
TABLE 4 ] Common Respiratory Pathogens in Addition to Core Respiratory Pathogensa That Can Cause
Community-Acquired Pneumonia in the Immunocompromised Patient and for Which Antimicrobial
Therapy Is Available
Bacteria Mycobacteria Viruses Fungi Parasites
Enterobacteriaceae (including those Mycobacterium Cytomegalovirus Pneumocystis Toxoplasma
producing ESBL, and also CRE) TB jirovecii gondii
Nonfermenting gram-negative bacilli (eg, Nontuberculous Herpes simplex Aspergillus Strongyloides
Pseudomonas or Acinetobacter) mycobacteria virus species stercoralis
MRSA Varicella-zoster Mucorales
virus species
Nocardia species Histoplasma
species
Rhodococcus equi Cryptococcus
species
Blastomyces
species
Coccidioides
species

CRE ¼ carbapenemase-producing Enterobacteriaceae; ESBL ¼ extended-spectrum b-lactamase. See Table 1 legend for expansion of other abbreviation.
a
As described in Table 3.

important. Another reason to perform broad
microbiologic studies is that treatment of opportunistic
pathogens is complex and often complicated by
toxicities and drug-drug interactions.
The extent of the microbiologic workup should be
individualized, considering the presence of risk factors
and likely organisms, as well as local capabilities. The
field of diagnostic microbiologic techniques has
experienced significant progress. The development of
rapid diagnostic tests using new molecular techniques
and sophisticated new laboratory methods, such as
matrix-assisted laser desorption ionization-time of flight
(MALDI-TOF) mass spectrometry, is reshaping the
clinical microbiology laboratory as well as our ability to
identify etiologic agents of CAP in
immunocompromised patients.19 A list of common
microbiologic studies with relevant clinical
considerations is depicted in Table 6.20-29
Question 6: When should bronchoscopy with
bronchoalveolar lavage be performed in hospitalized
patients with CAP who are immunocompromised?
We suggest that the decision to perform a bronchoscopy
or bronchoalveolar lavage should be individualized.
Bronchoscopy with BAL will be useful even in a
clinically unstable patient if the patient is at risk for
infection with multiple opportunistic pathogens and an
experienced team is available to perform the procedure.
Preferably, bronchoscopy with BAL should be done
early so that initial empirical therapy does not alter the
culture results. If the bronchoscopy can be done
promptly, a short delay before initiating antibiotic
therapy may be acceptable, given improved culture yield.
In general, the more immunocompromised the host, the
greater the potential benefit of performing
bronchoscopy with BAL.
If the etiology of CAP may be defined on the basis of
initial radiography and point-of-care diagnostic
testing, the small, but nevertheless clear risk associated
with bronchoscopy with BAL may outweigh the
benefit.30
Question 7: What microbiologic studies can be done with
BAL fluid from hospitalized patients with CAP who are
immunocompromised?
We suggest that microbiological studies in
bronchoalveolar lavage should be ordered according to
the presence of risk factors for particular pathogens.
In some institutions a fixed panel of tests is routinely
performed on BAL from immunocompromised patients
with CAP. In other institutions, the tests are ordered
considering the presence of clinical, radiographic, and
immunologic risk factors for specific organisms.
Table 731-35 lists microbiologic studies that can be done
on BAL or tissue from a transbronchial lung biopsy
together with relevant clinical considerations.

1902 CHEST Reviews [ 158#5 CHEST NOVEMBER 2020 ]

TABLE 5 ] Specific Immune Deficiencies and Associated Respiratory Pathogens
Specific Immune Deficiency Unique Respiratory Pathogen Associations
Neutropenia Pseudomonas aeruginosa, Stenotrophomonas maltophilia,
Enterobacteriaceae, Streptococcus mitis, Staphylococcus
aureus, Nocardia species, Aspergillus and other hyaline
molds (Scedosporium, Fusarium), yeast-like fungi
(Trichosporon), Mucorales species, dimorphic fungi
AIDS Pneumocystis jirovecii, Streptococcus pneumoniae,
Mycobacterium TB, M. avium-intracellulare complex, and
other nontuberculous mycobacteria, Histoplasma
capsulatum, Coccidioides, Bartonella, Rhodococcus,
Toxoplasma gondii, Cryptococcus neoformans,
Cryptosporidium, Nocardia, Talaromycosis marneffei,
Paracoccidioides, Burkholderia, cytomegalovirus,
Strongyloides
T-cell depletion (anti-thymocyte globulin, alemtuzumab) Pneumocystis jirovecii, Streptococcus pneumoniae,
Mycobacterium TB, M. avium-intracellulare complex, and
other nontuberculous mycobacteria, Aspergillus and other
hyaline molds, Mucorales species, varicella-zoster, herpes
simplex, cytomegalovirus, Histoplasma capsulatum,
Coccidioides, Bartonella species, Toxoplasma gondii,
Cryptococcus neoformans, Nocardia, Legionella,
Strongyloides
Hypogammaglobulinemia (common variable Respiratory viruses (influenza, respiratory syncytial virus,
immunodeficiency, multiple myeloma, therapies that human metapneumovirus, parainfluenza, adenovirus,
target CD19/20, eg, rituximab) enterovirus), encapsulated bacteria (S pneumoniae,
Moraxella catarrhalis, Haemophilus influenzae, S aureus,
Capnocytophaga, Pasteurella multocida), cytomegalovirus,
Pneumocystis
Calcineurin inhibitors (cyclosporine and tacrolimus) Legionella, Nocardia, Aspergillus and other hyaline molds,
Mucorales species, cytomegalovirus, endemic fungi
Antimetabolites (mycophenolate mofetil, azathioprine, Cytomegalovirus, varicella, respiratory viruses (if B-cell
6-MP, fludarabine) impairment), Legionella, Nocardia, Aspergillus and other
hyaline molds, Mucorales species, endemic fungi
(Pneumocystis post-fludarabine)
Mammalian target of rapamycin inhibitors (sirolimus, Cryptococcus, Pneumocystis
everolimus)
Tumor necrosis factor inhibitors Endemic fungi, Aspergillus, Mycobacterium (tuberculous and
nontuberculous), varicella-zoster, Nocardia, Pneumocystis
Janus kinase signaling inhibitors (eg, ibrutinib, dasatinib) Pneumocystis, mold, cytomegalovirus
Corticosteroids Bacteria, esp. Pseudomonas aeruginosa, Pneumocystis
jirovecii, Staphylococcus aureus, mycobacteria, Aspergillus
and other hyaline molds, Mucorales species,
cytomegalovirus, varicella-zoster, herpes simplex,
Histoplasma capsulatum, Coccidioides, Cryptococcus
neoformans, Nocardia, Legionella, Strongyloides
Other Natalizumab (Cryptococcus), vedolizumab (Mycobacterium
TB), tocilizumab (unknown), ustekinumab (theoretical
cytomegalovirus), secukinumab (theoretical mold),
eculizumab (Pseudomonas, mold), bortezomib (varicella-
zoster)

6-MP ¼ 6-mercaptopurine.

E. Empirical Therapy: General Principles We suggest that immunocompromised patients without

Question 8: What empirical therapy should be started in any additional risk factors for drug-resistant bacteria can
hospitalized patients with CAP who are receive initial empirical therapy targeting only the core
immunocompromised? respiratory pathogens.

chestjournal.org 1903
TABLE 6 ] Microbiologic Studies That Can Be Done in Immunocompromised Patients Hospitalized With
Community-Acquired Pneumonia
Studies References
Sputum samples for bacterial, mycobacterial, and fungal stains and cultures 20, 21
Comments: Sputum can be induced with inhaled isotonic or preferably hypertonic saline for certain pathogens
(eg, MTB, PCP) to avoid invasive procedures. Sputum samples can be tested by PCR for detection of MTB or
PCP
Nasopharyngeal swab with multiplex PCR for respiratory viruses 22, 23
Comments: A negative nasopharyngeal PCR result does not rule out viral pneumonia. If the suspicion is high,
perform the PCR on bronchoscopic samples. The finding of a virus by PCR does not rule out bacterial
infection
Nasopharyngeal swab with multiplex PCR for atypical bacteria .
Comments: Atypical pathogens such as Legionella, Chlamydophila, or Mycoplasma can also be identified in
oropharyngeal samples
Nasal PCR for MRSA .
Comments: Use in conjunction with a respiratory sample. A negative MRSA nasal PCR result, the absence of
gram-positive cocci in clusters on Gram stain, and a negative MRSA respiratory culture make MRSA
pneumonia extremely unlikely
Blood cultures times two (at least), 30 min apart 24, 25
Comments: If there is a port or central line or PICC line, to define the presence of line infection, perform blood
cultures from a peripheral vein and from the catheter lumens at the same time to calculate “time to
positivity.” The separation of samples over time improves bacterial detection in the case of intermittent
bacteremia
Urinary antigen for Streptococcus pneumoniae .
Comments: The recent administration of pneumococcal vaccine (within days) will produce a positive urinary
antigen result for Streptococcus pneumoniae
Urinary antigen for Legionella 26
Comments: Detects only Legionella pneumophila serotype 1. Other gram-negative bacteria may generate a
false positive test result. Obtain respiratory samples for culture and PCR to detect other species of
Legionella or serotypes if clinically indicated
Urinary antigen for Histoplasma capsulatum .
Comments: Very useful for disseminated disease. Cross-reaction with blastomycosis
Serum antigen for Cryptococcus neoformans .
Comments: A serum cryptococcal antigen test may produce a negative result for a patient with documented
cryptococcal pneumonia
Serum galactomannan antigen 27
Comments: Aspergillus cell wall contains the polysaccharide galactomannan. Also elevated in Fusarium,
Penicillium, blastomycosis, and histoplasmosis. False positive results may occur with IVIG, transfusions,
and some b-lactam antibiotics
Serum 1,3-b-D-glucan 27
Comments: b-D-Glucan is a cell wall component of several fungi. It screens for Aspergillus species, Candida
species, PCP, and other fungi. It does not detect mucormycosis. False positive results may occur with IVIG,
hemodialysis with cellulose, albumin, infections with Pseudomonas, and some b-lactam antibiotics
Swabs of vesicular or ulcerated skin lesions for viral PCR and cultures .
Comments: A positive PCR result for HSV or VZV from skin lesions is highly correlated with herpes or varicella-
zoster pneumonia
Biopsy of skin lesion for microbiology and pathology .
Comments: Sample must be sent to microbiology and pathology for stains and cultures for viruses, bacteria,
mycobacteria, fungi, and parasites
Viral load for CMV (PCR) 28
Comments: Obtain only if clinical suspicion is high. CMV reactivation is common in acute illness, and the
presence of copies of CMV in plasma does not necessarily indicate invasive disease. On the other hand, the
absence of viremia makes CMV pneumonitis less likely

(Continued)

1904 CHEST Reviews [ 158#5 CHEST NOVEMBER 2020 ]

TABLE 6 ] (Continued)
Studies
Viral load for adenovirus
Comments: Obtain only if clinical suspicion is high.
Serology for histoplasmosis, coccidioidomycosis, and blastomycosis
Comments: Fungal serology is not generally recommended in immunosuppressed patients because they fail
to generate an adequate antibody response to infection
CMV ¼ cytomegalovirus; HSV ¼ herpes simplex virus; IVIG ¼ IV immunoglobulin; MTB ¼ Mycobacterium TB; PCP ¼ Pneumocystis jirovecii pneumonia;
PCR ¼ polymerase chain reaction; PICC ¼ peripherally inserted central line catheter; VZV ¼ varicella-zoster virus. See Table 1 legend for expansion of other
abbreviation.
Although immunocompromised hosts may have unique
immunologic risk and often more frequent nosocomial
contact and antibiotic exposure, many
immunocompromised patients admitted with CAP do
not have any additional risk factors for drug-resistant
bacteria (eg, methicillin-resistant Staphylococcus aureus
[MRSA], Pseudomonas). For these patients, we suggest
initial empirical antimicrobial therapy targeting the core
respiratory pathogens described in Table 3. In this group
of patients, the initial empirical antibacterial therapy
would be the same as the initial empirical therapy for
hospitalized patients with CAP who are not
immunocompromised.1 Additional empirical treatment
beyond the core respiratory pathogens should be
considered according to the presence of risk factors for
drug-resistant or opportunistic pathogens and is
discussed in the sections below.
Question 9: In which patients with CAP who are
immunocompromised should empirical therapy be
extended beyond the core respiratory pathogens?
We suggest to extend empirical therapy beyond core
respiratory pathogens when (1) risk factors for drug-
resistant organisms or opportunistic pathogens are
present and (2) the delay in empirical antimicrobial
therapy will place the patient at increased risk of
mortality.
In addition to initial empirical treatment for core
respiratory pathogens, we suggest broader initial
coverage when the following factors are met: (1) A
resistant bacterium or an opportunistic pathogen is
suspected on the basis of the presence of risk factors
from findings on history or physical examination,
laboratory results, and/or imaging patterns; and (2)
waiting for microbiologic identification of the suspected
pathogen will significantly delay initiation of
antimicrobial therapy and may increase the risk of
mortality. Other considerations for extending initial
empirical therapy beyond core pathogens include
chestjournal.org
References
29
27
availability of point-of-care tests, severity of disease at
presentation, and use of prophylactic therapy for a
particular opportunistic pathogen.
The need for empirical therapy of opportunistic
pathogens will continue to evolve as more point-of-care
tests are developed for rapid diagnosis. Empirical
therapy beyond core respiratory pathogens may not be
necessary if the patient is clinically stable and the local
setting allows for rapid microbiologic diagnostic tests.
Question 10: What role does the severity of pneumonia
play in the selection of initial empirical therapy?
We suggest that the presence of severe pneumonia can be
used as an indication to start empirical therapy for
resistant gram-positive and gram-negative organisms,
followed by rapid deescalation if no multidrug-resistant
pathogen is identified.
Severity of illness is not by itself an accurate predictor of
drug resistance or opportunistic infection in pneumonia.
For example, Streptococcus pneumoniae is capable of
causing life-threatening septic shock, whereas invasive
pulmonary aspergillosis may present with an indolent,
progressive course.
The impact of severe pneumonia on empirical therapy is
the critical need to start early with an appropriate
antimicrobial therapy, because an initial inadequate
antibiotic spectrum has been identified as an
independent risk factor for mortality in CAP. Given this
circumstance, the presence of severe pneumonia or
pneumonia requiring ICU care can be used as a
threshold to start empirical therapy for resistant gram-
positive organisms (eg, MRSA) and resistant gram-
negative organisms (eg, Pseudomonas).
F. Empirical Therapy: Specific Pathogens
Question 11: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to MRSA?
1905
We suggest that initial empirical therapy to cover for
MRSA should be started in patients with a history of
colonization or infection with MRSA in the previous
12 months.
In patients with a history of colonization or infection
with MRSA in the previous 12 months, initial empirical
therapy should cover the possibility of infection due to
MRSA. There are other risk factors reported in the
literature for MRSA infection such as prior antibiotic
use, recent hospitalization, hemodialysis, or wound care,
but if the local prevalence of MRSA is low these risk
factors will each have a low positive predictive value and
should not be used to trigger empirical anti-MRSA
therapy.36-40 On the other hand, a single patient who
accumulates many of these risk factors may have a high
likelihood of CAP due to MRSA. Vancomycin or
linezolid are the first line for initial empirical therapy. In
regions with a high prevalence of MRSA, some members
of the panel will start empirical anti-MRSA therapy in
patients requiring ICU admission. A negative MRSA
result by nasal polymerase chain reaction (PCR),
absence of gram-positive cocci in clusters on Gram’s
staining, and a negative MRSA respiratory culture can
be used to deescalate anti-MRSA therapy.
Question 12: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to drug-resistant gram-
negative bacilli, including Pseudomonas aeruginosa?
We suggest that initial empirical therapy for
immunocompromised patients should cover resistant
gram-negative bacilli, including Pseudomonas
aeruginosa, if there is a history of colonization or
infection with a resistant gram-negative bacilli in the
prior 12 months, previous hospitalization with exposure
to broad-spectrum antibiotics, the presence of a
tracheostomy, neutropenia, or a history of pulmonary
comorbidity.
History of colonization or infection with a drug-resistant
gram-negative bacillus in the previous 12 months,
previous hospitalization with exposure to broad-
spectrum antibiotics, the presence of a tracheostomy,
neutropenia, a history of pulmonary comorbidity (eg,
cystic fibrosis, bronchiectasis, or recurrent exacerbations
of COPD requiring glucocorticoid and antibiotic use)
have been reported in the literature to increase the risk
of resistant gram-negative bacilli.37-42 Patients with any
of these risk factors should be considered for initial
empirical therapy against resistant gram-negative bacilli
including P aeruginosa. b-Lactam antibiotics with
1906 CHEST Reviews
activity against P aeruginosa, such as piperacillin-
tazobactam or a carbapenem, should be used as core
therapy. However, ceftazidime, which has no reliable
activity against S pneumoniae, should not be used as
monotherapy.43
Question 13: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to multidrug-resistant (MDR)
gram-negative bacilli?
We suggest that in patients with a recent history of
colonization or infection with MDR gram-negative
bacilli, the initial empirical therapy should cover the
possibility of infection due to the colonizing MDR gram-
negative bacilli.
In patients with a recent history of colonization or
infection with MDR gram-negative bacilli such as
extended-spectrum b-lactamase-producing
Enterobacteriaceae, carbapenemase-producing
Enterobacteriaceae, MDR Pseudomonas, or MDR
Acinetobacter, the initial empirical therapy should
cover the possibility of infection with the colonizing
MDR gram-negative bacilli. A knowledge of the local
susceptibility profile for gram-negative bacilli and the
most recent susceptibility profile of the colonizing
MDR gram-negative bacilli will help in the selection
of empirical therapy for these organisms with difficult-
to-treat resistance. For empirical therapy of MDR
gram-negative bacilli, b-lactam antibiotics such as
piperacillin-tazobactam or imipenem may have to be
changed to newer b-lactam antibiotics that have better
activity against some of the MDR bacteria. In these
patients, consideration should be given to the addition
of ceftazidime-avibactam, ceftolozane-tazobactam, or
meropenem-vaborbactam. Adding a polymyxin such
as colistin to a traditional b-lactam is a possibility
when other agents are not available. In patients
treated empirically with these broad-spectrum agents,
we strongly emphasize an extended microbiologic
workup and prompt deescalation of therapy if
appropriate.
Question 14: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to Pneumocystis jirovecii
pneumonia (PCP)?
We suggest initial empirical therapy should be extended
to cover the possibility of PCP in patients with diffuse,
bilateral, interstitial infiltrates or alveolar opacities and
who are not receiving PCP prophylaxis, and those who
[ 158#5 CHEST NOVEMBER 2020 ]
TABLE 7 ] Microbiologic Studies in BAL Fluid or Tranbronchial Lung Biopsy
Study Reference
Bacterial Gram stain and culture
Comments: A negative stain and culture of MDR pathogens (eg, MRSA) can be used for deescalation of therapy
unless antibiotics have been given for > 48 h
MRSA PCR
Comments: A negative PCR for MRSA can be used for deescalation of anti-MRSA therapy unless antibiotics 31
have been given for > 48 h
AFB stains and culture for tuberculous and nontuberculous mycobacteria
Comments: If positive AFB stain, nucleic acid amplification (NAA) tests allows for rapid diagnosis. NAA test can 20
be performed if the AFB stain is negative and the suspicion of disease is high
Nocardia stains and culture
Comments: AFB stain may be weakly positive
Fungal stains and culture
Comments: Because Aspergillus can colonize the airways, positive stains or culture of Aspergillus species from 27
respiratory samples do not necessarily indicate disease
PCP stains and PCR
Comments: In patients with PCP, the sensitivity of staining is higher in HIV-infected patients when compared 32
with HIV-uninfected patients. A positive PCR may occur in patients colonized with PCP. In non-HIV patients,
a negative PCR can be used to discontinue anti-PCP therapy
Respiratory viral panel with multiplex PCR
Comments: Viruses can be detected in BAL by PCR in a patient with a negative nasopharyngeal swab PCR for 22, 23
the same virus
Atypical pathogens panel with multiplex PCR
Comments: A positive PCR is considered diagnostic for atypical pneumonia because pathogens such as
Legionella, Chlamydophila, or Mycoplasma rarely colonize the airway
Galactomannan antigen
Comments: The cell wall of Aspergillus contains the polysaccharide galactomannan. Other fungi that contain 27
galactomannan include Histoplasma capsulatum, Penicillium species, and Fusarium species. False positive
levels may occur in BAL samples with some b-lactam antibiotics
Aspergillus PCR
Comments: The high sensitivity of PCR produces a high negative predictive value, making the diagnosis 27
unlikely with a negative test
(1,3)-b-D-Glucan
Comments: It is considered a poor screening tool for the diagnosis of invasive fungal infections because of its 27
low positive predictive value
CMV PCR
Comments: Quantitative PCR analysis in BAL fluid may help to differentiate between CMV pneumonia (high 33
viral load) vs CMV pulmonary shedding without pneumonia (low viral load), but cutoff levels are not defined
Cellular analysis
Comments: A predominantly inflammatory cellular pattern in the BAL with neutrophil pleocytosis can be used 34, 35
as a predictor of bacterial etiology
Histopathology
Comments: Routine hematoxylin and eosin staining, special stains, and culture for viruses, bacteria,
mycobacteria, fungi, and parasites

are either (1) HIV hosts who is newly diagnosed, or not
on antiretroviral therapy, or with CD4 counts less than
200 cells/mL (or a percentage lower than 14%) or (2) non-
HIV hosts with severely impaired cell-mediated immunity
(eg, taking glucocorticoids with cytotoxic agents).
In these patients we suggest the addition of
trimethoprim-sulfamethoxazole (TMP-SMX) to the
initial regimen. The recommended dosage for TMP-
SMX is 15 to 20 mg/kg/d of the trimethoprim
component orally or IV, given in three or four divided

chestjournal.org 1907
doses.44 The dose of TMP-SMX is the same for PCP in
the HIV-infected patient and PCP in the
immunocompromised non-HIV-infected patient.
Adjunctive glucocorticoids are recommended for HIV-
infected patients with room air PaO2 < 70 mm Hg and/
or an alveolar-arterial (A-a) oxygen gradient $
35 mm Hg.44 Corticosteroids are not beneficial in HIV-
negative patients with PCP.45
Question 15: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to Aspergillus?
We suggest that empirical therapy should cover the
possibility of pneumonia due to filamentous fungi such as
Aspergillus in patients with cancer and chemotherapy
with severe and prolonged neutropenia and a
radiographic nodular pattern surrounded by a halo of
ground-glass attenuation and/or cavitation.
Voriconazole is considered the first-line treatment for
patients with documented invasive aspergillosis, but we
do not suggest empirical voriconazole because these
patients are also at risk for other filamentous fungi
resistant to voriconazole (eg, those causing
mucormycosis).46 In these patients we suggest empirical
therapy with liposomal amphotericin at dosages of 5 to
7.5 mg/kg daily. In patients intolerant to amphotericin,
empirical therapy with isavuconazole at an initial dosage
of 200 mg every 8 h can be used as an alternative.47
Patients treated with tumor necrosis factor (TNF)
inhibitors, such as etanercept, infliximab, or
adalimumab, are also at risk of fungal pneumonia.11,12
In these patients we suggest an aggressive diagnostic
workup, and treat if a fungus is identified. In the
treatment of these patients it is important to discontinue
the use of the anti-TNF drug at the time of diagnosis of
pneumonia to improve the level of immunity of the
patient.
Question 16: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to Mucorales?
We suggest that empirical therapy should cover the
possibility of pneumonia due to filamentous fungi such as
Mucorales in patients with cancer and chemotherapy
with severe and prolonged neutropenia and a
radiographic nodular pattern, or a reverse halo sign, or
pleural effusion.
Empirical therapy for Mucorales is especially important
when fungal infection is suspected in a patient receiving
1908 CHEST Reviews
voriconazole antifungal prophylaxis. In these patients we
suggest liposomal amphotericin as part of the initial
empirical regimen at dosages of 5 to 7.5 mg/kg daily.48
In patients intolerant to amphotericin, empirical therapy
with isavuconazole at an initial dosage of 200 mg every
8 h can be used as an alternative.47 Voriconazole does
not cover mucormycosis, and therefore it is not
suggested as initial empirical therapy.
Question 17: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to Nocardia?
We suggest that empirical therapy should include the
possibility of Nocardia infection in patients with heart,
lung, liver, or hematopoietic stem cell transplant with
pneumonia and evidence for a lung or brain abscess,
and who have not been receiving prophylaxis with
TMP-SMX.
In these patients we suggest the addition of TMP-SMX
to the initial empirical therapy at a dosage of 15 mg/kg/
d of the trimethoprim component IV in three or four
divided doses.49 Resistance of Nocardia species to TMP-
SMX is a rare event.50 If TMP-SMX is contraindicated,
linezolid also has excellent activity and can be
considered for empirical therapy until susceptibilities are
known.50 If initial treatment already contains a drug
with activity against Nocardia species (eg, linezolid or
imipenem), empirical addition of TMP-SMX is not
requested. However, TMP-SMX is the drug of choice for
definite treatment.
Question 18: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to varicella-zoster virus?
We suggest that empirical therapy be extended to cover
the possibility of CAP due to varicella-zoster virus in
patients with bilateral reticulonodular infiltrates who also
have a vesicular rash.
In these patients we suggest the addition of IV acyclovir,
10 to 15 mg/kg IV every 8 h, to the initial empirical
regimen.51
Question 19: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to cytomegalovirus?
We suggest that empirical therapy be extended to cover
the possibility of CAP due to cytomegalovirus in patients
with bilateral interstitial pneumonia after a recent lung
transplant or hematopoietic stem cell transplant.
[ 158#5 CHEST NOVEMBER 2020 ]
In these patients we suggest the addition of ganciclovir
to the initial regimen at a dosage of 5 mg/kg IV every 12
h, with dose adjustment for renal dysfunction.52
Elevated plasma cytomegalovirus (CMV) viral loads are
frequent in patients with CMV pneumonitis, but this
finding alone is not sufficient for diagnosis.53 In lung
transplant recipients, CMV PCR viral load in BAL is a
superior diagnostic tool than plasma CMV viral load.54
Question 20: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to Mycobacterium
tuberculosis?
We suggest not to start empirical therapy to cover the
possibility of CAP due to Mycobacterium TB.
Pulmonary infections due to mycobacteria, such as TB,
are common in patients treated with TNF inhibitors and
patients with long-term high-dose steroids.11 But in the
case of suspected mycobacterial pneumonia we do not
suggest treating the patient with empirical therapy. We
suggest carrying out the indicated microbiologic studies
and beginning treatment once the pathogen has been
identified. We think that in these patients the risk-to-
benefit ratio of expanding empirical therapy with
multiple mycobacterial drugs, vs waiting to define which
patients have a mycobacterial infection, is in favor of
waiting for microbiologic results and treating them
specifically.
An exception to this approach would be in patients with
HIV infection with a history of recent exposure, who
have other clinical findings and radiographic features
compatible with TB infection, and who present with
severe CAP. In these patients we will start empirical
therapy for TB pending microbiologic workup.44
Question 21: In which immunocompromised patients
should the initial empirical therapy be extended to cover
the possibility of CAP due to parasites?
We suggest not to start empirical therapy to cover CAP
due to parasites.
Parasites that can produce CAP in the
immunocompromised host include Strongyloides
stercoralis and Toxoplasma gondii.55,56
Pneumonia in patients with Strongyloides hyperinfection
syndrome may be due to invasion of lung tissue by the
filariform larvae or with gram-negative bacteremia
secondary to seeding of the blood from the GI tract.
Patients at risk of Strongyloides hyperinfection
syndrome include those with solid organ
chestjournal.org
transplantation, hematopoietic stem cell transplantation,
or patients with high and prolonged dosages of
corticosteroids (eg, prednisone $ 20 mg/d, or its
equivalent, for longer than 1 month) in combination
with cytotoxic agents. Patients receiving this type of
immune-suppressing therapy, and also those with
secondary bacteremias, may not have an elevated
eosinophil count suggesting a parasitic infection.
Therapy with ivermectin is recommended for patients
with hyperinfection syndrome.55
Toxoplasma pneumonia occurs due to reactivation of
latent infection in (1) patients with HIV infection that is
newly diagnosed, and not undergoing antiretroviral
therapy or with CD4 counts less than 100 cells/mL; or (2)
patients with defects in cell-mediated immunity due to
high and prolonged doses of corticosteroids in
combination with cytotoxic agents. Therapy with
pyrimethamine and sulfadiazine is recommended for
patients with Toxoplasma pneumonia.44
We think that in these patients the risk-to-benefit ratio
of expanding empirical therapy for parasitic infections,
or waiting to define which patients have a parasitic
infection, favors waiting for microbiologic results and
treat only the patients with a proven parasitic infection.
Discussion
In this document we have developed general suggestions
for the initial treatment of the immunocompromised
patient who arrives at the hospital with pneumonia.
Despite our suggestions of empirical therapy for specific
pathogens in specific situations, we stress the
importance of making a concerted effort to establish a
rapid and accurate etiologic diagnosis and to deescalate
complex therapies once a presumptive pathogen is
properly ruled out. It is also important to consider local
susceptibility patterns when selecting empirical therapy.
The participants do suggest that, if evidence supports the
presence of infections that require highly specialized
management (eg, cytomegalovirus or Mucorales), after
initial therapy is begun, prompt transfer to a tertiary
care facility should be strongly considered. Transfer to a
specialized center may not be necessary if experienced
pulmonary and infectious disease specialists are
available to participate in management.
An important weakness of this document is the
simplification of heterogeneous conditions that affect
different arms of the immune system into a single group
of immunocompromised patients with CAP. Another
limitation is that we were not able to provide references
1909
that appropriately support several of our suggestions;
hence we need to emphasize that the suggestions offered
in this consensus are based primarily on expert opinion.
In conclusion, we have developed general suggestions
for the initial treatment of immunocompromised
patients hospitalized with pneumonia. When possible,
the care of these patients should be carried out by a
multidisciplinary group of specialists. Because
immunocompromised patients have been excluded from
prospective randomized studies of CAP treatment, there
is an urgent need to generate scientific evidence in this
field.
Acknowledgments
Author contributions: Development of first round of Delphi
questions and draft of the initial manuscript: J. A. R., D. M. M, S. E. E.,
C. D. C., K. A. C., and C. A. H. Development of all other rounds of
Delphi questions and subsequent versions of the manuscript: all
authors. Final version of the manuscript: J. A. R. and approved by all
authors.
Financial/nonfinancial disclosures: None declared.
Role of sponsors: The sponsor had no role in the design of the study,
the collection and analysis of the data, or the preparation of the
manuscript.
Additional information: The e-Appendix can be found in the
Supplemental Materials section of the online article.
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